Adenine bromination

One of the most important reactions of purines is the bromination of guanine or adenine at the C-8 position. It is this site that is the most common point of modification for bioconjugate techniques using purine bases (Figure 1.53). Either an aqueous solution of bromine or the compound N-bromosuccinimide can be used for this reaction. The brominated derivatives then can be used to couple amine-containing compounds to the pyrimidine ring structure by nucleophilic substitution (Chapter 27, Section 2.1). 

Additionally, C8 can have sufficient electron density to allow the attack of electrophiles. This is promoted by an electron-donating group attached to the ring system. As a consequence, adenine reacts with bromine to give an 8-bromo derivative whereas purine forms only an adduct. It has been reported that the guanine moiety within DNA can be attacked by electrophiles causing mutagenicity. 

Bromination has been widely studied and occurs readily with adenine, guanine, hypoxan-thine, xanthine, and methylated xanthines giving the 8-bromo analogs. 

Base analogs such as 5-bromouracil and 2-aminopurine can be incorporated into DNA and are even more likely than normal nucleic acid bases to form transient tautomers that lead to transition mutations. 5-Bromouracil, an analog of thymine, normally pairs with adenine. However, the proportion of 5-bromouracil in the enol tautomer is higher than that of thymine because the bromine atom is more electronegative than is a methyl group on the C-5 atom. Thus, the incorporation of 5-bromouracil is especially likely to cause altered base-pairing in a subsequent round of DNA replication (Figure 27.42). 

Ejfect of anions on capacitance pits. The presence of bromine, iodine and sulphate anions in the cytosine solutions can induce the two-dimensional condensation of cytosine at the electrically neutral electrode surface [66]. The halogen ions can induce a new potential region of condensation also with adenine [67]. The two-dimensional condensation of adenine induced by bromine ions is much slower than the condensation of adenine molecules alone [67], Fig. 6. 

The total synthesis of quantamycin [61], necessitated the development of methodology to create a somewhat strained tra j-peihydrofuropyran structure with the required appendages. The adenine moiety was attached by a unique method whereby a bicyclic thioglycoside was treated sequentially with N-benzoyl adenine and bromine [62]. Quantamycin was found to have approximately 8-10% inhibition of binding of lincomycin or erythromycin at the same concentration to ribosomes from Streptomyces. However, no in vitro antibacterial activity was found, which may be an intrinsic problem, or a pharmacodynamic effect due to improper partitioning. 

Bromoacetylpyridine is prepared by bromination of commercially available ["CJacetylpyridine (labeled in the carbonyl carbon). With the other compounds shown in Table II, the halogen is also inserted (usually by direct halogenation) in the last step of the synthesis. In the recently described synthesis of 3-chloroacetylpyridine adenine dinucleotide, the immediate precursor is the corresponding 3-diazomethylketone. The diazo group is then exchanged for chlorine by treatment with lithium chloride in hydrochloric acid, a procedure similar to one used for the preparation of halomethylketone derivatives of amino acids. " ... 

In enzymic assays, 3-acetylpyridine adenine dinucleotide (3-APAD) can replace NAD as substrate. No one has as yet succeeded in the direct bromination to form 3-bromo-APAD, although 3-chloro-APAD has been synthesized. If the ribose of the functional moiety of 3-APAD is replaced by a hydrocarbon chain, the redox potential is altered to —320 mV, a magnitude close to that of NAD+ Compounds of this structure can be easily labeled by using methyl or carbonyl-labeled acetylpyridine for synthesis. 

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